Imidazo[1,2-a]pyrazin-8-ylamines, method of making, and method of use thereof

ABSTRACT

A novel composition comprises a compound of Formula 1 
                 
 
the pharmaceutically acceptable salts, hydrates, solvates, crystal forms, diastereomers, prodrugs, or mixtures thereof. The composition is of particular utility in the treatment of kinase-implicated disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefits of U.S. Provisional PatentApplication Ser. No. 60/374,213 filed Apr. 19, 2002, which is fullyincorporated herein by reference.

BACKGROUND

This invention relates to certain imidazo[1,2-a]pyrazin-8-ylamines andrelated compounds, which when appropriately substituted are modulatorsof kinase activity. This invention also relates to pharmaceuticalcompositions comprising such compounds, and to the use of such compoundsin treating a variety of kinase-associated disorders. Additionally, thisinvention relates to the use of such compounds as probes for theidentification of kinases of therapeutic interest.

One of the central post-translational control elements in eukaryoticsignal transduction is the phosphorylation of the hydroxyl moiety ofserine, threonine, or tyrosine. The phosphorylation state of a givenprotein can govern its enzyme activity, stability, protein-proteinbinding interactions, and cellular distribution. Phosphorylation anddephosphorylation is thus a “chemical switch” that allows the cell totransmit signals from the plasma membrane to the nucleus, and toultimately control gene expression. Although the exact mechanisms ofsignal transduction have yet to be elucidated, kinases are involved inthe control of cell metabolism, growth, differentiation, and apoptosis.These signaling mechanisms affect the onset of cancer, metabolicdisorders (for example diabetes), inflammation, immune system disorders,and neurodegeneration. Certain kinases have been implicated in cellproliferation and carcinogenesis. For example, many human cancers arecaused by disregulation of a normal protein (e.g., when a proto-oncogeneis converted to an oncogene through a gene translocation). Becausekinases are key regulators they are ideal drug design targets.

Inhibitors of kinases are among the most important pharmaceuticalcompounds known. Tyrosine kinase inhibitors are useful in inhibitingT-cell proliferation, and thus they are useful as immunosuppressiveagents for the prevention or treatment of graft rejection followingtransplant surgery and for the prevention or treatment of autoimmunediseases such as rheumatoid arthritis and psoriasis. Other tyrosinekinase inhibitors have been described, for example, in U.S. Pat. No.5,593,997 to Dow et al. Erlotinib (CP-358774) teach a quinazolinederivative under development as an orally active epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitor for treatment of solid tumorsincluding non-small cell lung cancer (NSCLC), pancreatic cancer, breastcancer, and neck cancer. Gleevec and Imatinib (STI-571), from Novartis,are tyrosine kinase inhibitors indicated for treatment of chronicmyelogenous leukemia (CML), prostate tumors, and gastrointestinalstromal tumors, among others. AstraZeneca is developing gefitinib(ZD-1839; Iressa), an inhibitor of epidermal growth factor receptor 1(EGFR1) tyrosine kinase, for the potential treatment of cancers whichover-express EGF receptors, including non-small cell lung cancer (NSCLC)and other solid tumors such as breast tumors. CEP-1347 (Cephalon Inc.)is an indolcarbazole choline acetyltransferase inhibitor and c-junN-terminal kinase inhibitor for treatment of Alzheimer's disease,Parkinson's disease, and AIDS-related peripheral neuropathy. Cephalon isalso developing CEP-701, an orally active tyrosine kinase inhibitor forthe potential treatment of prostate and other cancers. A PDGF receptortyrosine kinase inhibitor (SU-101, leflunomide) is being investigatedfor treatment of various cancers and rheumatoid arthritis. Sugen hasalso investigated the anti-cancer effects of the FLK-1 tyrosine kinaseinhibitor Semaxanib, particularly for colorectal and lung cancers,leukemia, Kaposi's sarcoma, and others.

Serine/threonine kinase inhibitors are also pharmaceutically important.Eli Lilly is developing LY333531 (ruboxistaurin), an inhibitor ofprotein kinase C beta, for treatment of diabetic macular edema anddiabetic retinopathy. Flavopirodol (Aventis) is a synthetic flavonoidinhibitor of cyclin-dependent kinases, is under development fortreatment of mantle cell lymphoma (MCL) and fludar refractory chroniclymphocytic leukemia (CLL). One Raf kinase inhibitor (BAY-43-9006,Bayer) is in development for treatment of solid tumors and myeloidleukemia, and another (ISIS 5132, Isis) is being investigated fortreatment of ovarian cancer. Several p38 mitogen-activated proteinkinase inhibitors (VX-745, VX-702, and VX-850, Vertex, and SCIO-469,Scios) have been investigated for treatment of inflammation, rheumatoidarthritis, and myelodysplastic syndrome (MDS).

Highly selective, cell-permeable modulators of one or more individualkinases would thus be useful in the treatment of variouskinase-implicated disorders. Such compounds would also be useful for thesystematic investigation of the cellular function of one or morekinases, and thus, would provide invaluable tools for the identificationof various kinases of therapeutic interest.

The compounds most closely related structurally to those describedherein are a series of imidazolopyrazines described in WO 02/060492, asJAK inhibitors for the treatment of immune disorders. A series ofpiperazinylimidazo[1,2a]pyrazines are described by Lumma J. Med. Chem.1983, 26, 357-363 as displaying affinity for α-adrenergic receptors.Other imidazo[1,2-a]pyrazines have been reported to be useful asbronchodilators and phosphodiesterase inhibitors (see, for example,Bioorg. Med Chem. 1999, pages 1059-1065). Effects on pulmonaryhypertension have also been reported (see, for example, J. Cardiovase.Pharmacol. 1998, volume 32, no. 2, pages 213-219). The compoundsdescribed in these publications are not within the scope of the presentinvention.

SUMMARY

In one embodiment, this invention is directed to a compositioncomprising a compound of Formula 1:

the pharmaceutically acceptable salts, hydrates, solvates, crystalforms, diastereomers, prodrugs, or mixtures thereof,

wherein R₁ is hydrogen; cyclo-(C₃-C₆ alkyl)-methyl; straight or branchedchain C₁-C₇ alkyl, in which the branched alkyl chains may form a 3 to 7member heteroalkyl or alkyl ring; sulfonamide; C₁-C₆ alkoxy;(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; mono- or di(C₁-C₆ alkyl)amino; mono- ordi(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); or phenyl or heteroaryl ring whichmay be unsubstituted, or mono-, di- or trisubstituted with one or moreof hydroxy, nitro, cyano, amino, sulfonamide, halogen, C₁-C₆ alkyl,C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, mono- or di(C₁-C₆ alkyl)amino, or mono-or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); and,

R₂ is straight or branched chain C₁-C₇ alkyl, in which the branchedalkyl chains may form a 3-7 member heteroalkyl or alkyl ring;cyclo-(C₃-C₆ alkyl)-methyl; C₁-C₆ alkoxy, except when Z₂ is phenyleneand A is 0 and R₁ is straight or branched chain C₁-C₇ alkyl (but notcycloalkyl), phenyl, or phenyl substituted with hydroxy, nitro, cyano,amino, C₁-C₆ alkoxy, or halogen, or when Z₂ is phenylene and A is 1, Z₁is —C(R₄)(R₅)— wherein m is 1, 2, or 3 and R₁ is straight or branchedchain C₁-C₇ alkyl (but not cycloalkyl), phenyl, or phenyl substitutedwith hydroxy, nitro, cyano, amino, C₁-C₆ alkoxy, or halogen, or when Z₂is —C(R₇)(R₈)— wherein n is 1, 2, or 3, each occurrence of R₇ and R₈ isindependently straight or branched chain C₁-C₆ alkyl or halogen and R₂is C₁-C₆ alkoxy or phenyl substituted with nitro;(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; or phenyl or heteroaryl which may beunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro (except when Z₂ is phenylene and A is 0 and R₁ is straight orbranched chain C₁-C₇ alkyl (but not cycloalkyl), phenyl, or phenylsubstituted with hydroxy, nitro, cyano, amino, C₁-C₆ alkoxy, or halogen,or when A is 1 and Z₁ is —C(R₄)(R₅)— wherein m is 1, 2, or 3, and R₁ isstraight or branched chain C₁-C₇ alkyl (but not cycloalkyl), phenyl, orphenyl substituted with hydroxy, nitro, cyano, amino, C₁-C₆ alkoxy, orhalogen, or when Z₂ is phenylene and A is 1 and Z, is —C(R₄)(R₅)—wherein m is 1, 2, or 3 and R₁ is straight or branched chain C₁-C₇ alkyl(but not cycloalkyl), phenyl, or phenyl substituted with hydroxy, nitro,cyano, amino, C₁-C₆ alkoxy, or halogen, or when Z₂ is —C(R₇)(R₈)—wherein n is 1, 2, or 3, each occurrence of R₇ and R₈ is independentlystraight or branched chain C₁-C₆ alkyl or halogen and R₂ is C₁-C₆ alkoxyor phenyl substituted with nitro), cyano, amino, halogen, C₁-C₆ alkyl,C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- ordi(C₁-C₆ alkyl)amino, or amino(C₁-C₆ alkyl); phenyoxy phenyl where eachphenyl may be independently unsubstituted, mono-, di- or trisubstitutedwith one or more of hydroxy, nitro, cyano, amino, halogen, sulfonamide,C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆ alkyl)amino, oramino(C₁-C₆ alkyl); phenyl or heteroaryl piperazine where the phenyl orheteroaryl ring may be independently unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, sulfonamide, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- ordi(C₁-C₆ alkyl)amino, or mono- or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl);

R₃ is hydrogen; straight or branched chain C₁-C₇ alkyl, in which thebranched alkyl chains may form a 3-7 member heteroalkyl or alkyl ring;

Z₁ is

wherein

-   -   A is O or 1;    -   each occurrence of R₄ and R₅ is independently hydrogen, straight        or branched chain C₁-C₆ alkyl, sulfonamide, or halogen;    -   m is 0, 1, or 2; and    -   R₆ is hydrogen; straight or branched chain C₁-C₆ alkyl; phenyl        which may be unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen, C₁-C₆        alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆        alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆        alkyl)amino, or amino(C₁-C₆ alkyl); or heteroaryl which may be        unsubstituted, mono-, di- or trisubstituted with one or more of        hydroxy, nitro, cyano, amino, halogen, C₁-C₆ alkyl, C₁-C₆        perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,        (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆ alkyl)amino,        or amino(C₁-C₆ alkyl); and

Z₂ is a divalent linking group selected from para-phenylene,meta-phenylene, ortho-phenylene, or naphthylene, and

wherein

-   -   each occurrence of R₇ and R₈ is independently straight or        branched chain C₁-C₆ alkyl, sulfonamide, or halogen;    -   n is 0,1, 2, or 3; and    -   R₉-R₁₂ are each independently hydrogen; straight or branched        chain C₁-C₆ alkyl; phenyl which may be unsubstituted, mono-, di-        or trisubstituted with one or more of hydroxy, nitro, cyano,        amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,        (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆ alkyl)amino,        or amino(C₁-C₆ alkyl); or heteroaryl which may be unsubstituted,        mono-, di- or trisubstituted with one or more of hydroxy, nitro,        cyano, amino, halogen, C₁-C₆ alkyl, C₁-C₆        alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆        alkyl)amino, or amino(C₁-C₆ alkyl).

In another embodiment, a pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula 1 and apharmaceutically acceptable carrier.

In still another embodiment, a method of treating a kinase-implicateddisorder in a mammal comprises administration to the mammal of apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula 1 and a pharmaceutically acceptable carrier.

In another embodiment, a method for identifying a kinase comprisescontacting an organism, cell, or preparation comprising the kinase witha compound of Formula 1, and detecting modulation of the kinaseactivity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustrating one synthesis of the presentcompounds.

FIG. 2 is a schematic illustrating another synthesis of the presentcompounds.

DETAILED DESCRIPTION

The compounds of Formula 1 are novel compounds belonging to the familyof imidazo[1,2-a]pyrazines. Without wishing to be bound to anyparticular theory, it is believed that the interaction of the compoundsof Formula 1 with a kinase (i.e., one or more kinases) results inmodulation of the activity of the kinase(s). The compounds of Formula 1are thus expected to have therapeutic application in mammaliankinase-implicated conditions. As used herein, “modulation” refers to achange in kinase activity as a direct or indirect response to thepresence of a compound of Formula 1, relative to the activity of thekinase in the absence of the compound. The change may be an increase inactivity or a decrease in activity, and may be due to the directinteraction of the compound with the kinase, or due to the interactionof the compound with one or more other factors that in turn affectkinase activity. For example, the presence of the compound may increaseor decrease kinase activity by directly binding to the kinase, bycausing (directly or indirectly) another factor to increase or decreasethe kinase activity, or by (directly or indirectly) increasing ordecreasing the amount of kinase present in the cell or organism.

In one preferred embodiment, novel imidazo[1,2-a]pyrazines may comprisecompounds of general Formula 2:

the pharmaceutically acceptable salts, hydrates, solvates, crystalforms, diastereomers, prodrugs, or mixtures thereof.

In Formula 2, R₁ is hydrogen; cyclo-(C₃-C₆ alkyl)-methyl; straight orbranched chain C₁-C₇ alkyl, in which the branched alkyl chains areallowed to also form a 3-7 member heteroalkyl or alkyl ring;sulfonamide; C₁-C₆ alkoxy; (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; mono- ordi(C₁-C₆ alkyl)amino, or mono- or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); orphenyl or heteroaryl ring which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,sulfonamide, halogen, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, mono- or di(C₁-C₆ alkyl)amino, or mono-or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl).

R₂ in Formula 2 is straight or branched chain C₁-C₇ alkyl, in which thebranched alkyl chains are allowed to also form a 3-7 member heteroalkylor alkyl ring; cyclo-(C₃-C₆ alkyl)-methyl; C₁-C₆ alkoxy except when A is0 and R₁ is straight or branched chain C₁-C₇ alkyl (but not cycloalkyl),phenyl, or phenyl substituted with hydroxy, nitro, cyano, amino, C₁-C₆alkoxy, or halogen, or when A is 1 and Z₁ is —C(R₄)(R₅)— wherein m is 1,2, or 3 and R₁ is straight or branched chain C₁-C₇ alkyl (but notcycloalkyl), phenyl, or phenyl substituted with hydroxy, nitro, cyano,amino, C₁-C₆ alkoxy, or halogen; (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; phenylor heteroaryl which may be unsubstituted, mono-, di- or trisubstitutedwith one or more of hydroxy, nitro, (except when A is 0 and R₁ isstraight or branched chain C₁-C₇ alkyl (but not cycloalkyl), phenyl, orphenyl substituted with hydroxy, nitro, cyano, amino, C₁-C₆ alkoxy, orhalogen, or when A is 1 and Z₁ is —C(R₄)(R₅)— wherein m is 1, 2, or 3and R₁ is straight or branched chain C₁-C₇ alkyl (but not cycloalkyl),phenyl, or phenyl substituted with hydroxy, nitro, cyano, amino, C₁-C₆alkoxy, or halogen)cyano, amino, halogen, C₁-C₆ alkyl, C₁-C₆perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆ alkyl)amino,amino(C₁-C₆ alkyl); phenyoxy phenyl where each phenyl may beindependently unsubstituted, mono-, di- or trisubstituted with one ormore of hydroxy, nitro, cyano, amino, halogen, sulfonamide, C₁-C₆ alkyl,C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆ alkyl)amino, oramino(C₁-C₆ alkyl); or phenyl or heteroaryl piperazine where the phenylor heteroaryl ring may be independently unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,halogen, sulfonamide, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- ordi(C₁-C₆ alkyl)amino, or mono- or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl).

R₃ in Formula 2 may be hydrogen; straight or branched chain C₁-C₇ alkyl,in which the branched alkyl chains can also form a 3-7 memberheteroalkyl or alkyl ring.

A in Formula 2 is 0 or 1.

Z₁ in Formula 2 is

wherein

-   -   each occurrence of R₄ and R₅ is independently hydrogen, straight        or branched chain C₁-C₆ alkyl, sulfonamide, or halogen;    -   m is 1, 2, or 3; and    -   R₆ is hydrogen; straight or branched chain C₁-C₆ alkyl; phenyl,        which may be unsubstituted, mono-, di- or trisubstituted with        one or more of hydroxy, nitro, cyano, amino, halogen, C₁-C₆        alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆        alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆        alkyl)amino, or amino(C₁-C₆ alkyl); or heteroaryl, which may be        unsubstituted, mono-, di- or trisubstituted with one or more of        hydroxy, nitro, cyano, amino, halogen, C₁-C₆ alkyl, C₁-C₆        perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,        (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆ alkyl)amino,        or amino(C₁-C₆ alkyl).

In another preferred embodiment, the novel imidazo[1,2-a]pyrazinescomprise compounds of general Formula 3:

the pharmaceutically acceptable salts, hydrates, solvates, crystalforms, diastereomers, prodrugs, or mixtures thereof.

In Formula 3, a is 0, 1, 2 or 3. R₁₄ is hydrogen; cyclo-(C₃-C₆alkyl)-methyl; straight or branched chain C₁-C₆ alkyl, in which thebranched alkyl chains may form a 3-7 member heteroalkyl or alkyl ring;sulfonamide; C₁-C₆ alkoxy; (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; mono- ordi(C₁-C₆ alkyl)amino, mono- or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); orphenyl or heteroaryl ring, which may be unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro, cyano, amino,sulfonamide, halogen, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, mono- or di(C₁-C₆ alkyl)amino, or mono-or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl).

R₂ in Formula 3 is straight or branched chain C₁-C₆ alkyl, in which thebranched alkyl chains may form a 3-7 member heteroalkyl or alkyl ring;cyclo-(C₃-C₆ alkyl)-methyl; C₁-C₆ alkoxy except where R₁ is hydrogen,C₁-C₆ alkoxy, or phenyl substituted with nitro;(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; phenyl or heteroaryl, which may beunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro, cyano, amino, halogen, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- ordi(C₁-C₆ alkyl)amino, or amino(C₁-C₆ alkyl); phenyoxy phenyl, in whicheach phenyl may be independently unsubstituted, mono-, di- ortrisubstituted with one or more of hydroxy, nitro (except where R₁ ishydrogen, C₁-C₆ alkoxy, or phenyl substituted with nitro), cyano, amino,halogen, sulfonamide, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- ordi(C₁-C₆ alkyl)amino, or amino(C₁-C₆ alkyl); or phenyl or heteroarylpiperazine, in which the phenyl or heteroaryl ring may be independentlyunsubstituted, mono-, di- or trisubstituted with one or more of hydroxy,nitro, cyano, amino, halogen, sulfonamide, C₁-C₆ alkyl, C₁-C₆perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono- or di(C₁-C₆ alkyl)amino, or mono-or di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl).

R₃ is hydrogen; straight or branched chain C₁-C₆ alkyl, in which thebranched alkyl chains may form a 3-7 member heteroalkyl or alkyl ring.

As used herein, when any variable occurs more than one time in theformulas, its definition on each occurrence is independent of itsdefinition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference to “a” kinase or “the”kinase is inclusive of one or more kinases.

By “heteroaryl” is meant aromatic systems containing at least oneheteroatom, for example, oxygen, nitrogen, sulfur, and the like, as wellas combinations comprising at least one of the foregoing heteroatoms.Suitable heteroaryl groups include, for example (as numbered from thelinkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl,2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl,2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl,thiazolinyl, thiadiazolinyl, tetrazolyl, and the like.

By “heteroalkyl” is meant an aliphatic ring containing at least 1 carbonatom in addition to 1-3 heteroatoms independently selected from oxygen,sulfur, or nitrogen, and the like, as well as combinations comprising atleast one of the foregoing heteroatoms.

By “sulfonamide” is meant —S(O)₂N— in either S-linked or N-linkedorientation, wherein the nitrogen atom can be unsubstituted; or mono- ordisubstituted with cyclo-(C₃-C₆ alkyl)-methyl or straight or branchedchain C₁-C₇ alkyl, in which the branched alkyl chains may form a 3-7member alkyl or heteroalkyl ring.

By “piperazine” is meant unsubstituted piperazine, as well aspiperazines independently substituted on 1-4 carbon atoms with hydroxy,cyano, amino, halogen, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, mono- or di(C₁-C₆ alkyl)amino, mono- ordi(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), or sulfonamide.

By “C₁-C₆ alkyl” is meant straight or branched chain alkyl groups orcycloalkyl groups having 1-6 carbon atoms, such as, for example, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl,and the like. Preferred C₁-C₆ alkyl groups are methyl, ethyl, propyl,butyl, cyclopropyl, cyclopropylmethyl, cyclohexyl, cycloheptyl, andnorbornyl.

By “C₁-C₆ alkoxy” is meant an alkyl group of the indicated number ofcarbon atoms attached through an oxygen bridge such as, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. Preferred alkoxy groups herein are C₁-C₄alkoxy groups.

The term “halogen” includes fluorine, chlorine, bromine, and iodine.

If the compounds of Formula 1 have asymmetric centers, then Formula 1includes all of the optical isomers and mixtures thereof. In addition,compounds with carbon-carbon double bonds may occur in Z- and E-forms,with all isomeric forms of the compounds being included. These compoundscan be, for example, racemates or optically active forms. In thesesituations, the single enantiomers, i.e., optically active forms, can beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. Where a compound ofFormula 1 exists in various tautomeric forms, the invention is notlimited to any one of the specific tautomers, and includes alltautomeric forms of the compound.

Representative compounds of the present invention, which are encompassedby Formula 1, include, but are not limited to their pharmaceuticallyacceptable acid addition salts. Non-toxic “pharmaceutically acceptablesalts” include, but are not limited to salts with inorganic acids, suchas hydrochlorate, phosphate, diphosphate, hydrobromate, sulfate,sulfinate, nitrate, or like salts; or salts with an organic acid, suchas malate, maleate, fumarate, tartrate, succinate, citrate, acetate,lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate,benzoate, salicylate, stearate, and alkanoate such as acetate,HOOC—(CH₂)_(n)—COOH where n is 0-4, and like salts. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium, and ammonium.

In addition, if the compound of Formula 1 is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, it maybe produced by dissolving the free base in a suitable organic solventand treating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts encompassed by Formula I.

Prodrugs of the compounds of Formula 1 are also within the scope of thepresent invention, for example acylated prodrugs of the compounds ofFormula 1. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare non-toxic pharmaceuticallyacceptable acylated and other prodrugs of the compounds encompassed byFormula 1.

Methods for obtaining the compounds described herein are known to thoseof ordinary skill in the art, suitable procedures being described, forexample, in the references cited herein.

As mentioned above, it is believed that the interaction of the compoundsof Formula 1 with one or more kinases results in modulation of theactivity of the one or more kinases. Suitable kinases include but arenot limited to tyrosine kinases and serine/threonine kinases, which maybe classified as including the AGC group (cyclic nucleotide regulatedfamily) of protein kinases, which includes the cyclic nucleotideregulated protein kinase family (e.g., PKA and PKG), thediacylglycerol-activated/phospholipid-dependent family protein kinase Cfamily (e.g., PKC), the PKA and PKC-related family (e.g., RAC and Akt),the kinases that phosphorylate G protein-coupled receptors family, thebudding yeast AGC-related protein kinase family, the kinases thatphosphorylate ribosomal protein S6 family, the budding yeast DBF2/20family, the flowering plant PVPK1 protein kinase homolog family, andother AGC related kinase families.

The CaMK (calcium calmodulin dependent) group of protein kinasesincludes kinases regulated by Ca²⁺/CaM and close relatives family, theKIN1/SNF1/Nim1 family, and other related CaMK related kinase families.The CMGC group (named because it includes the cyclin-dependent kinases)includes the cyclin-dependent kinases (e.g., CDKs) and close relativesfamily, the ERK (e.g., MAP) kinase family, the glycogen synthase 3(e.g., GSK3) family, the casein kinase II family, the Clk family andother CMGC kinases.

The PTK group of protein kinases includes protein-tyrosine kinases thatmay be nonmembrane-spanning or membrane-spanning tyrosine kinases. ThePTK group of protein kinases includes the Src family, the Tek/Atkfamily, the Csk family, the Fes (Fps) family, the Abl family, theSyk/ZAP70 family, the Ttk2/Jak1 family, the Ack family, the focaladhesion kinase (Fak) family, the epidermal growth factor receptorfamily, the Eph/Elk/Eck receptor family, the Axl family, the Tie/Tekfamily, the platelet-derived growth factor receptor family, thefibroblast growth factor receptor family, the insulin receptor family,the LTK/ALK family, the Ros/Sevenless family, the Trk/Ror family, theDDR/TKT family, the hepatocyte growth factor receptor family, thenematode Kin15/16 family and other PTK kinase families.

The OPK group (other protein kinases) includes the Polo family, theMEK/STE7 family, the PAK/STE20 family, the MEKK/STE11 family, the NimAfamily, the wee1/mik1 family, the kinases involved in transcriptionalcontrol family, the Raf family, the Activin/TGFb receptor family, theflowering plant putative receptor kinases and close relatives family,the PSK/PTK leucine zipper domain family, the casein kinase I family,the PKN prokaryotic protein kinase family and other OPK protein kinasefamilies. A large number of kinases are found in G. Hardie et al.,Protein Kinase Facts Book 0-12-324719-5 (1995).

Accordingly, a method of treating a kinase-implicated disease orcondition in a mammal, preferably a human, comprises administration tothe mammal of a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula 1 and a pharmaceuticallyacceptable carrier. As used herein “therapeutically effective” includesalleviation of disease, disease symptoms, preventative, and prophylactictreatment.

Kinases are implicated in a large variety of diseases, as certainmutations in protein kinases can lead to activation of pathways causing,for example, the production of tumors, while other mutations in proteinkinases block pathways and prevent a response. Some diseases that arelinked to mutations in protein kinases are listed in the KinMutBasedatabase (http://www.uta.fi/imt/bioinfo/KinMutBase/) (Stenberg et al.,Nucleic Acids Research, Vol. 28, pp. 369-372, 2000). Diseases caused byprotein kinase mutations include X-linked agammaglobulinemia (XLA), andnon-insulin dependent diabetes mellitus (NIDDM), and severe combinedimmunodeficiency (SCID). Mutations related to tumor development havebeen liked to such diseases as Hirschprung's disease, multiple endocrineneoplasia type 2 (MEN2) a and b, medullary thyroid carcinoma (FMTC),papillary renal carcinoma (HPRC), and Peutz-Jeghers syndrome.

Mutations in growth factor receptor kinases are linked to diseases suchas mastocytosis, systemic mast cell disease, piebaldism,hypochondroplasia, thanatophoric dysplasia, and skeletal dysplasia.Other protein kinase-linked diseases include Coffin-Lowry syndrome,congenital insensitivity to pain with anhidrosis (CIPA), hypertension,vascular dysplasia, errors in vascular morphogenesis, and X-linkedmental retardation. Mutations in protein kinases have also been linkedto neurodegenerative diseases such as amyotrophic lateral sclerosis(ALS) and Alzheimer's disease (AD).

Other diseases associated with protein kinases include Gaucher disease,hypochromic anemia, granulomatous disease, ataxia-telangiectasia,familial hypercholesterolemia, certain types of muscular dystrophy suchas Driefuss-Emory type, cystic fibrosis, type 1 hyperlipoproteinemia,Treacher Collins Franceschetti syndrome 1, Tay-Sachs disease, type 1neurofibromatosis, adenomatous polyposis of the colon, X-linkedichthyosis, and Beckwith-Weidemann Syndrome.

Altered PKA (cyclic AMP-dependent protein kinase) expression isimplicated in a variety of disorders and diseases including cancer,thyroid disorders, diabetes, atherosclerosis, and cardiovasculardisease. Altered MAP (mitogen-activated protein) kinase expression isimplicated in a variety of disease conditions including cancer,inflammation, immune disorders, and disorders affecting growth anddevelopment. RTKs (receptor tyrosine kinases), CDKs and STKs(serine/threonine kinases) have all been implicated in a host ofpathogenic conditions including, significantly, large number of diversecancers. Others pathogenic conditions that have been associated withPTKs include, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis,angiogenesis, restinosis, ocular diseases, rheumatoid arthritis andother inflammatory disorders, autoimmune disease, and a variety of renaldisorders.

Preferably, the conditions, diseases and/or disorders that can beaffected using compounds of Formula 1 and compositions comprising suchcompounds include, but are not limited to, psoriasis, cancer (forexample, chronic myelogenous leukemia, gastrointestinal stromal tumors,non-small cell lung cancer, breast cancer, ovarian cancer, recurrentovarian cancer, prostate cancer such as hormonal refractory prostatecancer, kidney cancer, head and neck cancer, or colorectal cancer),immunoregulation (graft rejection), atherosclerosis, rheumatoidarthritis, Parkinson's disease, Alzheimer's disease, diabetes (forexample insulin resistance or diabetic retinopathy), septic shock, andthe like.

In a preferred embodiment, the condition is cancer. A method of treatingcancer comprising administering to a mammal in need thereof atherapeutically effective amount of a compound of Formulas 1, 2, or 3and a therapeutically effective amount of an antitumor therapeutic.Treatment with the antitumor therapeutic may be prior to treatment withthe inventive compounds, during treatment, following treatment with thecompounds, or a combination thereof. Suitable antitumor therapeutics areknown, and are preferably a chemotherapeutic agent, for examplemitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide,doxorubicin, or a combination comprising at least one of the foregoingchemotherapeutic agents. Radiotherapeutic antitumor agents may also beused, alone or in combination with chemotherapeutic agents.

In another embodiment, pharmaceutical compositions comprising at leastone compound of Formula 1, together with one or more non-toxic,pharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. Such pharmaceuticalcompositions include packaged pharmaceutical compositions for treatingdisorders responsive to modulation of kinase activity. A packagedpharmaceutical composition includes a container holding atherapeutically effective amount of at least compound of Formula 1 andinstructions (e.g., labeling) indicating that the contained compositionis to be used for treating a disorder responsive to kinase modulation inthe patient. Those of ordinary skill in the art will also recognize awide variety of non-toxic pharmaceutically acceptable solvents that maybe used to prepare solvates of the compounds of the invention, such aswater, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide(DMSO).

The compounds of Formula 1 may be administered orally, topically,parenterally, by inhalation or spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles. Oral administration in theform of a pill, capsule, elixir, syrup, lozenge, troche, or the like isparticularly preferred. The term parenteral as used herein includessubcutaneous injections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. The pharmaceutical compositions containingcompounds of Formula 1 may be in a form suitable for oral use, forexample, as tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents, which may be a naturally-occurringphosphatide, for example, lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent, and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring, and coloringagents, may also be present.

Suitable pharmaceutical compositions for therapeutic use may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin, or mixtures of these. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents that have been mentioned above. Thesterile injectable preparation may also be sterile injectable solutionor suspension in a non-toxic parentally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compounds of general Formula 1 may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of Formula 1 may be administered parenterally in a sterilemedium. The drug, depending on the vehicle and concentration used, caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as local anesthetics, preservatives, and buffering agentscan be dissolved in the vehicle.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It is convenient toformulate these animal feed and drinking water compositions so that theanimal takes in an appropriate quantity of the composition along withits diet. It is also convenient to present the composition as a premixfor addition to the feed or drinking water.

Dosage levels of the order of from about 0.1 milligram to about 140milligram per kilogram of body weight per day are useful in thetreatment of the above-indicated conditions (about 0.5 milligram toabout 7 gram per human patient per day). The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. Dosage unit forms will generally contain betweenfrom about 1 mg to about 500 milligram of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. For the treatmentof eating disorders, including obesity, a dosage regimen of 1 or 2 timesdaily is particularly preferred. For the treatment of impotence a singledose that rapidly reaches effective concentrations is desirable. It willbe understood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

Preferred compounds of the invention will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding, and desirablein vitro and in vivo half-lives. Penetration of the blood brain barrierfor compounds used to treat CNS disorders is necessary, while low brainlevels of compounds used to treat peripheral disorders are oftenpreferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B 1996, volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition 1998, volume 26, pages 1120-1127).

In another embodiment, the compounds of Formula 1 are also useful asprobes for the localization of kinases of therapeutic interest, that is,for both in vivo and in vitro identification and isolation the specificproteins to which it binds. A method for identifying a kinase comprisescontacting an organism, cell, or preparation comprising the kinase withcompound or salt according to Formulas 1, 2, or 3, and detectingmodulation of an activity of the kinase. Suitable methods for detectingkinase modulation are known, for example those described herein.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1 Synthesis of Compounds of Formula 1 (FIG. 1)

6,8-dibromoimidazo[1,2-a]pyrazine (3). A solution of 1.00 equivalents(eq.) of 3,5-dibromo-2-aminopyrazine 1 in ethanol is treated with 2.00eq. of α-bromoaldehyde 2 at room temperature (RT) and heated for 48hours (hr). The solvent is removed under reduced pressure and theresidue is triturated with diethyl ether and filtered to give the HBrsalt 3.

8-Amino-6-bromoimidazo[1,2-a]pyrazine (4). Procedure 1: A mixture of

1.00 eq. of 6,8-imidazo[1,2-a]pyrazine 3 in 28% ammonia/water solutionor 40% aqueous methyl amine is heated to between 80 to 90° C. for 24 hr.The resulting mixture is partitioned between CH₂Cl₂ and H₂O. The aqueouslayer is extracted with CH₂Cl₂ and the combined organic extracts aredried over Na₂SO₄. The solvent is removed under reduced pressure and theresulting residue is crystallized from ethanol to yield 4.

Procedure 2: A solution of 1.00 eq. of 6,8-imidazo[1,2-a]pyrazine 3 inN,N-dimethylacetamide is treated with 2.00 eq. of benzylamine and 3.00eq. of K₂CO₃. The resulting mixture is heated to 100° C. for 24 to 48hours, cooled to RT and partitioned between H₂O/CH₂Cl₂. The aqueouslayer is extracted with CH₂Cl₂ and combined organic extracts are driedover Na₂SO₄. The solvent is removed under reduced pressure and theresulting residue is purified by flash chromatography (3:7 ethyl acetate(EtOAc)/Hexanes) to yield 4.

8-Amino-6-aryl-imidazo[1,2-a]pyrazine (5). A mixture of 1.00 eq. of8-amino-6-bromoimidazo[1,2-a]pyrazine, 3.00 eq. of R₄-substitutedboronic acid, and 0.10 eq. of Pd (PPh_(3b))₄, in 6.00 eq. of 1NNa₂CO₃/dme is heated to 90° C. for 24 hr. The mixture is cooled to RTand partitioned between 10% acetic acid (AcOH)/CH₂Cl₂. The aqueous phaseis extracted with CH₂Cl₂ and combined extracts are dried over Na₂SO₄.The solvent is removed under reduced pressure and the resulting residueis purified by flash chromatography (1-5% 2M NH₃/methanol/CH₂Cl₂) toyield 5.

EXAMPLE 2 Synthesis of Compounds of Formula 1b (FIG. 2).

8-Amino-6-aryl-imidazo[1,2-a]pyrazine (6). A mixture of 1.00 eq. of8-amino-6-bromoimidazo[1,2-a]pyrazine, 3.00 eq. of R₄-sustituted boronicacid, and 0.10 eq. of Pd (PPh₃)₄, in 4.00 eq. of 1N Na₂CO₃/dme is heatedto 90° C. for 24 hr. The mixture is cooled to RT and partitioned betweenEtOAc/saturated NaHCO₃. The aqueous phase is extracted with EtOAc andthe combined extracts are dried over Na₂SO₄. The solvent is removedunder reduced pressure and the resulting residue is purified by flashchromatography (1-5% 2M NH₃/methanol/EtOAc) to yield 6.

N-[3-(8-Benzylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide (8). Asolution of 1.00 eq. of 8-amino-6-aryl-imidazo[1,2-a]pyrazine intoluene/DMA is treated dropwise with 1.00 eq. of aryl acid chloride andstirred at RT for 10 hr. The resulting mixture is partitioned betweenEtOAc/saturated NaHCO₃. The aqueous phase is extracted with EtOAc andthe combined extracts are dried over Na₂SO₄. The solvent is removedunder reduced pressure and the resulting residue is purified by flashchromatography (1-5% methanol/EtOAc) to yield 8.

N-[3-(8-Benzylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzenesulfonamide(9). A solution of 1.00 eq. of 8-amino-6-aryl-imidazo[1,2-a]pyrazine in5% N-methyl morpholine (NMM)/toluene is treated dropwise with 1.1 eq ofaryl sulfonyl chloride and heated to 50° C. for 8 h. The solution iscooled to RT and partitioned between EtOAc/saturated NaHCO₃. The aqueousphase is extracted with EtOAc and the combined extracts are dried overNa₂SO₄. The solvent is removed under reduced pressure and the resultingresidue is purified by flash chromatography ((1-5% methanol/EtOAc) toyield 9.

1-[3-(8-Benzylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-phenyl-urea(10). A solution of 1.00 eq. of 8-amino-6-aryl-imidazo[1,2-a]pyrazine in5% NMM/toluene is treated dropwise with 1.0 eq of aryl isocyanate andheated to 60° C. for 8 hr. The solution is cooled to RT and partitionedbetween EtOAc/saturated NaHCO₃. The aqueous phase is extracted withEtOAc and the combined extracts are dried over Na₂SO₄. The solvent isremoved under reduced pressure and the resulting residue is purified byflash chromatography (1-5% 2M NH₃/MeOH/EtOAc) to yield 10.

EXAMPLE 3

The following compounds were prepared in accordance with FIGS. 1 and 2using the above procedures.

-   -   (a)        1-(4-Chloro-phenyl)-3-[3-(8-methylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF=C₂₀H₁₇ClN₆O, MW=392.84 Mass Spec m/z (M⁺+1) 393.06.    -   (b)        1-(4-Chloro-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF=C₂₅H₁₉ClN₆O MW=454.91 Mass Spec m/z (M⁺+1) 455.04.    -   (c)        1-(4-Chloro-phenyl)-3-{3-[8-(4-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₅H₁₈Cl₂N₆O, MW−489.36 Mass Spec m/z (M⁺+1) 489.20.    -   (d)        1-(4-Chloro-phenyl)-3-{3-[8-(3-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₅H₁₈Cl₂N₆O, MW−489.36 Mass Spec m/z (M⁺−1) 489.13.    -   (e)        1-(4-Chloro-phenyl)-3-{3-[8-(2-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₅H₁₈Cl₂N₆O, MW=489.36 Mass Spec m/z (M⁺+1) 489.04.    -   (f)        1-(4-Chloro-phenyl)-3-{3-[8-(pyridin-3-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₄H₁₈ClN₇O, MW=455.90 Mass Spec m/z (M⁺+1) 456.07.    -   (g)        1-{3-[8-(4-Chloro-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-urea,        MF=C₂₆H₂₀Cl₂N₆O, MW=503.38 Mass Spec m/z (M⁺+1) 503.04.    -   (h)        1-{3-[8-(3-Chloro-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-urea,        MF=C₂₆H₂₀Cl₂N₆O, MW=503.38 Mass Spec m/z (M⁺+1) 503.01.    -   (i)        1-{4-[8-(4-Chloro-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-urea,        MF=C₂₆H₂₀Cl₂N₆O, MW=503.38 Mass Spec m/z (M⁺+1) 503.01.    -   (j)        1-{4-[8-(3-Chloro-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-urea,        MF=C₂₆H₂₀Cl₂N₆O, MW=503.38 Mass Spec m/z (M⁺+1) 503.01.    -   (k)        4-(6-{3-[3-(4-Chloro-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic        acid ethyl ester, MF=C₂₈H₂₃ClN₆O₃, MW=526.97 Mass Spec m/z        (M⁺+1) 527.05.    -   (l)        Cyclopropylmethyl-[6-(4-phenoxy-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-amine,        MF=C₂₂H₂₀N₄O, MW=356.42 Mass Spec m/z (M⁺+1) 357.19.    -   (m)        (2-Methoxy-benzyl)-[6-(4-phenoxy-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-amine,        MF=C₂₆H₂₂N₄O₂, MW=422.48 Mass Spec m/z (M⁺+1) 423.19.    -   (n)        Benzo[1,3]dioxol-5-ylmethyl-[6-(4-phenoxy-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-amine,        MF=C₂₆H₂₀N₄O₃, MW=436.46 Mass Spec m/z (M⁺+1) 437.18.    -   (o)        [6-(4-Chloromethyl-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methoxy-benzyl)-amine,        MF=C₂₁H₁₉ClN₄O, MW=378.85 Mass Spec m/z (M⁺+1) 379.13.    -   (p)        1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-phenyl-urea,        MF=C₂₇H₂₄N₆O₂, MW=464.52 Mass Spec m/z (M⁺+1) 465.07.    -   (q)        (2-Methoxy-benzyl)-{6-[4-(4-methoxy-benzylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl}-amine,        MF=C₂₈H₂₇N₅O₂, MW=465.55 Mass Spec m/z (M⁺+1) 466.10.    -   (r)        (2-Methoxy-benzyl)-{6-[3-(4-methoxy-benzylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl}-amine,        MF=C₂₈H₂₇N₅O₂, MW=465.55 Mass Spec m/z (M⁺+1) 466.09.    -   (s)        1-{3-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-phenyl-urea,        MF=C₂₇H₂₄N₆O₂, MW=464.52 Mass Spec m/z (M⁺+1) 465.05.    -   (t)        1-(2-Chloro-phenyl)-3-{4-[8-(2-methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₇H₂₃ClN₆O₂, MW=498.96 Mass Spec m/z (M⁺+1) 499.18.    -   (u)        1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-phenyl)-urea,        MF=C₂₈H₂₆N₆O₃, MW=494.54 Mass Spec m/z (M⁺+1) 495.22.    -   (v)        1-{4-[8-(2-Methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-methoxy-phenyl)-urea,        MF=C₂₈H₂₆N₆O₃, MW=494.54 Mass Spec m/z (M⁺+1) 495.21.    -   (w)        4-{6-[4-(Piperidine-1-carbonyl)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoic        acid ethyl ester, MF=C₂₇H₂₇N₅O₃, MW=469.54 Mass Spec m/z (M⁺+1)        470.08.    -   (x)        4-(6-{3-[3-(4-Chloro-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic        acid ethyl ester, MF=C₂₈H₂₃ClN₆O₃, MW=526.97 Mass Spec m/z        (M⁺+1) 527.05.    -   (y)        4-(6-{3-[3-(2-Methylsulfanyl-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic        acid ethyl ester, MF=C₂₉H₂₆N₆O₃S, MW=538.62 Mass Spec m/z (M⁺+1)        539.18.    -   (z)        {4-[8-(4-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-piperidin-1-yl-methanone,        MF=C₂₄H₂₂ClN₅O, MW=431.92 Mass Spec m/z (M⁺+1) 432.03.    -   (aa)        {4-[8-(2-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-piperidin-1-yl-methanone,        MF=C₂₄H₂₂ClN₅O, MW=431.92 Mass Spec m/z (M⁺+1) 432.03.    -   (bb)        3-Methoxy-N-{4-[8-(2-methoxy-benzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide,        MF=C₂₈H₂₅N₅O₃, MW=479.53 Mass Spec m/z (M⁺+1) 479.99.    -   (cc)        1-(3-Chloro-4-fluoro-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF=C₂₅H₁₈ClFN₆O, MW=472.90 Mass Spec m/z (M⁺+1) 473.01.    -   (dd)        1-(4-Chloro-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF=C₂₅H₁₉ClN₆O, MW=454.91 Mass Spec m/z (M⁺+1) 455.04.    -   (ee)        1-[3-(8-Phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea,        MF=C₂₆H₁₉F₃N₆O, MW=488.46 Mass Spec m/z (M⁺+1) 489.01.    -   (ff)        1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea,        MF=C₂₆H₁₈ClF₃N₆O, MW=522.91 Mass Spec m/z (M⁺+1) 523.11.    -   (gg)        1-(4-Chloro-phenyl)-3-{3-[8-(4-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₅H₁₈Cl₂N₆O, MW=489.36 Mass Spec m/z (M⁺+1) 489.20.    -   (hh)        1-{3-[8-(4-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea,        MF=C₂₆H₁₈ClF₃N₆O, MW=522.91 Mass Spec m/z (M⁺+1) 523.13.    -   (ii)        1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(3-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₅H₁₇Cl₂FN₆O, MW=507.35 Mass Spec m/z (M⁺+1) 507.13.    -   (jj)        1-(4-Chloro-phenyl)-3-{3-[8-(3-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₅H₁₈Cl₂N₆O, MW=489.36 Mass Spec m/z (M⁺+1) 489.13.    -   (kk)        1-{3-[8-(3-Chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea,        MF=C₂₆H₁₈ClF₃N₆O, MW=522.91 Mass Spec m/z (M⁺+1) 523.12.    -   (ll)        1-(3-Chloro-4-fluoro-phenyl)-3-{3-[8-(2-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea,        MF=C₂₅H₁₇Cl₂FN₆O, MW=507.35 Mass Spec m/z (M⁺+1) 507.09.

EXAMPLE 4

A generalized description the standard AKT-1 Kinase Assay that may beused to evaluate the inventive compounds is as follows.

In a final reaction volume of 40 microliters (μl), active recombinantN-terminus his-tagged AKT-1/PKBα kinase expressed in Sf21 cells (UBI#14-276; 50-100 nanogram; 19-38 nanomolar; about 4.5-9 mU) was incubatedin 25 mM Tris pH 7.6; 5 mM Beta-glycerophosphate; 2 mM DTT; 100 μMsodium vanadate; 10 mM MgCl₂ in 96-well Pierce Reaci-Bind™streptavidin-coated high binding capacity coated white plate (Pierce#15502) coated with saturating amounts of biotinylated Crosstide peptide(UBI #12-385; biotin-KGSGSGRPRTSSFAEG; 50 picomoles; about 1.25 μM) andinitiated with the addition of 2.5 μCi ³²P-γATP (specific activity 3000Cu/mmole; 10 mCi/ml; about 21 nM). Compounds were tested initially induplicate wells for determination of initial IC₅₀ inhibition in half logserial dilutions starting at 100 μM with a final concentration of 2%DMSO. Following a 30 min incubation at 30° C., the reaction was stoppedby aspiration and 4×100 μl washes with TBS plus 0.05% Tween-20 prior toaddition of 100 μl scintillant and counting in Beckman TopCountinstrument. Percent inhibition was calculated as [1-((AVE CPM_(compound)-AVE CPM _(no peptide background))/(AVE CPM_(no compound MAX)-AVE CPM _(no peptide background))))* 100].Staurosporine, a general ATP competitive kinase inhibitor was used as areference compound and showed an IC50 of approximately 60-100 nM forAKT-1 in the current assay format. Approximate S/N ratios are 8-12× withAVE CPM of Maximum about 15 k and no peptide background about 1.5 K.Improved S/N ratios can be obtained using higher amounts of either AKT-1kinase or ³²P-γATP. Cold ATP was not added in current format but hasbeen added at up to 200 μM in the presence of 5 μCi ³²P-γATP resultingin S/N ratios of approximately 5-10×.

EXAMPLE 5

A generalized description the standard assay to evaluate modulation ofcell growth in soft agar (using cell lines HCT-15 (colon cancer),MiaPaca2 (pancreatic cancer), MCF-7 (breast cancer) and a NIH3T3 clonestably over-expressing transfected myrAkt-1 human gene, for example) isas follows.

Preparation of the agar base layer: A quantity of 500 ml of 2×DMEM(phenol red free, Sigma Cat #D2902) is prepared, and sterile filtered.To that solution is added 10 ml of sodium pyruvate (Gibco, Cat#11360-070), 10 ml of penicillin/streptomycin (Gibco, Cat#15140-122), 10ml of Glutamax (Gibco, cat# 33050-061) and 100 ml of heat-inactivatedFBS (Gemini) to make 2×DMEM complete media stock. Two stockconcentrations of Sea Plaque low melt agar (Biowhittaker, Cat #431097),1%, and 0.6%, are prepared with ultra pure milliQ water, and sterilizedby autoclaving. To prepare the agar base layer for a 12-well plate(Falcon #353042), 6 ml of the 2×DMEM stock is mixed with 6 ml of 1% agarstock, both at 37° C., and 1 ml of the resulting mixture is added toeach well of the 12 well plate, 3 hrs prior to setup of top layer.

Top layer with cells and compound for evaluation: Cells at 60-80%confluency (log growth) in T75 are trypsinized with 1 ml of 1× trypsinsolution (Gibco), neutralized with 10 ml of 1×DMEM 10% FBS and viablecells counted using a hemocytometer via trypan blue exclusion. A workingstock of 2.5×10⁴ cells/ml is prepared in 1×DMEM 10% FBS. A 15 mlcentrifuge tube is prepared for each concentration of compound tested induplicate wells of a 12 well plate. The following are added in order: 1ml of 2×DMEM stock at 37° C.; compound at 2× final desired concentration(using 4 microliter volume from a 1000× concentrated dilution series in100% DMSO); followed by 2,500 cells (using 100 microliters of 1×10⁴cell/ml working stock), and finally 1 ml of 0.6% agar stock at 37° C.Following careful mixing, 1 ml each is added to duplicate wells of the12-well plate. The plate is then placed in a 37° C., 5% CO₂, humidifiedincubator for 10 to 14 days and read. Rapid diffusion of CPD throughouttop and bottom agar layer results in final drug concentration of 1×.

Counting Colonies: After 10 days of incubation, the plates are removedfrom the incubator for photography and colony counting. Each well isscanned using an eyepiece with a micrometer guide and 5× phase optics.Colonies 50 micrometer or greater in diameter are scored as positive.Duplicate wells are averaged and percent inhibition calculated usingnumber of colonies in no compound control wells as 100%.

All compounds described in Examples 1-3 were tested in accordance withthe protocols of Examples 4-5 and determined to exhibit an IC₅₀ valueless than or equal to 25 micromolar.

All cited references are incorporated herein in their entirety. Whilepreferred embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations.

1. At least one chemical entity chosen from compounds of Formula 10

and pharmaceutically acceptable salts, hydrates, and diastereomers,wherein R₁ is chosen from phenyl and substituted phenyl, wherein saidsubstituted phenyl is chosen from mono-, di- and trisubstituted phenyls,and wherein substituents are independently chosen from hydroxy, nitro,cyano, amino, sulfonamide, halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); and R₂ is chosen from phenyl and substitutedphenyl, wherein said substituted phenyl is chosen from mono-, di- andtrisubstituted phenyls and wherein substitutents are chosen fromhydroxy, nitro, cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy,mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and amino(C₁-C₆ alkyl); R₃is chosen from hydrogen; and straight and branched chain C₁-C₇ alkyls,in which the branched alkyl chains may form a 3-7 member ring chosenfrom heteroalkyl rings and alkyl rings; and A is chosen from 0 and
 1. 2.At least one chemical entity chosen from compounds of Formula 8

and pharmaceutically acceptable salts, hydrates, and diastereomers,wherein R₁ is chosen from phenyl and substituted phenyl, wherein saidsubstituted phenyl is chosen from mono-, di- and trisubstituted phenylsand wherein substituents are independently chosen from hydroxy, nitro,cyano, amino, sulfonamide, halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); and R₂ is chosen from phenyl and substitutedphenyl, wherein said substituted phenyl is chosen from mono-, di- andtrisubstituted phenyls, and wherein substituents are independentlychosen from hydroxy, nitro, cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, and amino(C₁-C₆ alkyl); R₃ is chosen from hydrogen; andstraight and branched chain C₁-C₇ alkyls, in which the branched alkylchains may form a 3-7 member ring chosen from heteroalkyl rings andalkyl rings; and A is chosen from 0 and
 1. 3. At least one chemicalentity chosen from compounds of Formula 9:

and pharmaceutically acceptable salts, hydrates, and diastereomers,wherein R₁ is chosen from phenyl and substituted phenyl, wherein saidsubstituted phenyl is chosen from mono-, di- and trisubstituted phenylsand wherein substituents are independently chosen from hydroxy, nitro,cyano, amino, sulfonamide, halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); and R₂ is chosen from phenyl and substitutedphenyl, wherein said substituted phenyl is chosen from mono-, di- andtrisubstituted phenyls and wherein substituents are independently chosenfrom hydroxy, nitro, cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, and amino(C₁-C₆ alkyl); R₃ is chosen from hydrogen; andstraight and branched chain C₁-C₇ alkyls, in which the branched alkylchains may form a 3-7 member ring chosen from heteroalkyl rings andalkyl rings; and A is chosen from 0 and
 1. 4. At least one chemicalentity chosen from compounds of Formula 2

and pharmaceutically acceptable salts, hydrates, and diastereomers,wherein R₁ is chosen from hydrogen; cyclo-(C₃-C₆ alkyl)-methyl; straightand branched chain C₁-C₇ alkyls, in which the branched alkyl chains mayform a 3-7 member ring chosen from heteroalkyl rings and alkyl rings;sulfonamide; C₁-C₆ alkoxy; C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; mono(C₁-C₆alkyl)amino; di(C₁-C₆ alkyl)amino; mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl);di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); phenyl; heteroaryl; substitutedphenyl, wherein said substituted phenyl is chosen from mono-, di-, andtrisubstituted phenyls and wherein substituents are independently chosenfrom hydroxy, nitro, cyano, amino, sulfonamide, halo, C₁-C₆ alkyl, C₁-C₆perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, mono(C₁-C₆alkyl)amino; di(C₁-C₆ alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl);and di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); and substituted heteroaryl,wherein said substituted heteroaryl is chosen from mono-, di- andtrisubstituted heteroaryls wherein substituents are independently chosenfrom hydroxy, nitro, cyano, amino, sulfonamide, halo, C₁-C₆ alkyl, C₁-C₆perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, mono(C₁-C₆alkyl)amino, di(C₁-C₆ alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl);and di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); R₂ is chosen from straight andbranched chain C₁-C₇ alkyls, in which the branched alkyl chains may forma 3-7 member ring chosen from heteroalkyl rings and alkyl rings;cyclo-(C₃-C₆ alkyl)-methyl; C₁-C₆ alkoxy except when A is 0 and R₁ ischosen from straight and branched chain C₁-C₇ alkyls (but notcycloalkyl), phenyl, and substituted phenyl wherein substituents areindependently chosen from hydroxy, nitro, cyano, amino, C₁-C₆ alkoxy,and halo, and when A is 1 and Z₁ is —C(R₄)(R₅)— wherein m is chosen from1, 2, and 3 and R₁ is chosen from straight and branched chain C₁-C₇alkyls (but not cycloalkyl), phenyl, and substituted phenyl whereinsubstituents are independently chosen from hydroxy, nitro, cyano, amino,C₁-C₆ alkoxy, and halo; (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; phenyl;substituted phenyl, wherein said substituted phenyl is chosen frommono-, di-, and trisubstituted phenyls and wherein substituents areindependently chosen from hydroxy, nitro, cyano, amino, sulfonamide,halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, mono(C₁-C₆alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl);heteroaryl, and substituted heteroaryl, wherein said heteroaryl group ischosen from mono-, di- and trisubstituted heteroaryls and whereinsubstituents are independently chosen from hydroxy, nitro (except when Ais 0 and R₁ is chosen from straight and branched chain C₁-C₇ alkyls (butnot cycloalkyl), phenyl, and substituted phenyl wherein substituents areindependently chosen from hydroxy, nitro, cyano, amino, C₁-C₆ alkoxy,and halo; and except when A is 1 and Z₁ is —C(R₄)(R₆)— wherein m ischosen from 1, 2, and 3, and R₁ is chosen from straight and branchedchain C₁-C₇ alkyls (but not cycloalkyl), phenyl, substituted phenylwherein substituents are independently chosen from hydroxy, nitro,cyano, amino, C₁-C₆ alkoxy, and halo), cyano, amino, halo, C₁-C₆ alkyl,C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, and amino(C₁-C₆ alkyl); phenyoxy phenyl; substitutedphenyoxy phenyl, where each phenyl is independently chosen from mono-,di- and trisubstituted phenyls wherein substituents are independentlychosen from hydroxy, nitro, cyano, amino, halo, sulfonamide, C₁-C₆alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆)alkylamino), di(C₁-C₆alkyl)amino, and amino(C₁-C₆ alkyl); phenyl piperazine; substitutedphenyl piperazine, wherein the phenyl ring of said substituted phenylpiperazine is chosen from mono-, di-, and trisubstituted phenyls andwherein substitutents are chosen from hydroxy, nitro, cyano, amino,halo, sulfonamide, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy,mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, mono(C₁-C₆alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl);heteroaryl piperazine; and substituted heteroaryl piperazine where theheteroaryl ring of said substituted heteroaryl piperazine is chosen frommono-, di- and trisubstituted heteroaryls wherein substituents areindependently chosen from hydroxy, nitro, cyano, amino, halo,sulfonamide, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy,C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy mono(C₁-C₆ alkyl)amino,di(C₁-C₆ alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); R₃ is chosen from hydrogen; straight andbranched chain C₁-C₇ alkyls, in which the branched alkyl chains can alsoform a 3-7 member ring chosen from heteroalkyl rings and alkyl rings; Ais chosen from 0 and 1; and Z₁ is chosen from

wherein each occurrence of R₄ and R₅ is independently chosen fromhydrogen, straight and branched chain C₁-C₆ alkyl, sulfonamide, andhalo; m is chosen from 1, 2, and 3; and R₆ is chosen from hydrogen;straight and branched chain C₁-C₆ alkyl; phenyl; substituted phenyl,wherein said substituted phenyl is chosen from mono-, di- andtrisubstituted phenyls and wherein substituents are independently chosenfrom hydroxy, nitro, cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, and amino(C₁-C₆ alkyl); heteroaryl, and substitutedheteroaryl, which said substituted heteroaryl is chosen from mono-, di-and trisubstituted heteroaryls and wherein substituents areindependently chosen from hydroxy, nitro, cyano, amino, halo, C₁-C₆alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, and amino(C₁-C₆ alkyl).
 5. At least one chemical entitychosen from compounds of Formula 3:

and pharmaceutically acceptable salts, hydrates, and diastereomers,wherein a is chosen from 0, 1, 2 and 3; R₁₄ is chosen from hydrogen;cyclo-(C₃-C₆ alkyl)-methyl; straight and branched chain C₁-C₆ alkyl, inwhich the branched alkyl chains may form a 3-7 member ring chosen fromheteroalkyl rings and alkyl rings; sulfonamide; C₁-C₆ alkoxy;(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy; mono(C₁-C₆ alkyl)amino; di(C₁-C₆alkyl)amino; mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl); di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); phenyl; substituted phenyl chosen from mono-,di-, and trisubstituted phenyls and wherein substituents areindependently chosen from hydroxy, nitro, cyano, amino, sulfonamide,halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, mono(C₁-C₆alkyl)amino(C₁-C₆ alkyl); and di(C₁-C₆ alkyl)amino(C₁-C₆ alkyl);heteroaryl; and substituted heteroaryl wherein said substitutedheteroaryl is chosen from mono-, di- and trisubstituted heteroaryls andwherein substituents are independently chosen from hydroxy, nitro,cyano, amino, sulfonamide, halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); R₂ is chosen from straight and branched chainC₁-C₆ alkyls, in which the branched alkyl chains may form a 3-7 memberring chosen from heteroalkyl rings and alkyl rings; cyclo-(C₃-C₆alkyl)-methyl; C₁-C₆ alkoxy; phenyl; substituted phenyl wherein saidsubstituted phenyl is chosen from mono-, di-, and trisubstituted phenylsand wherein substituents are independently chosen from hydroxy, nitro,cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy,mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and amino(C₁-C₆ alkyl);heteroaryl; and substituted heteroaryl, wherein said substitutedheteroaryl is chosen from mono-, di- and trisubstituted heteroaryls andwherein substituents are independently chosen from hydroxy, nitro,cyano, amino, halo, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy,mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and amino(C₁-C₆ alkyl);phenyoxy phenyl; substituted phenoxy phenyl, in which each phenyl isindependently chosen from mono-, di- and trisubstituted phenyls andwherein substituents are independently chosen from hydroxy, nitro,cyano, amino, halo, sulfonamide, C₁-C₆ alkyl, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy, (C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy,mono(C₁-C₆ alkyl)amino, di(C₁-C₆ alkyl)amino, and amino(C₁-C₆ alkyl);phenyl piperazine, substituted phenyl piperazine, wherein said phenylring of said substituted phenyl piperazine is chosen from mono-, di-,and trisubstituted phenyls and wherein substituents are independentlychosen from hydroxy, nitro, cyano, amino, halo, sulfonamide, C₁-C₆alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); heteroaryl piperazine; and substitutedheteroaryl piperazine wherein said heteroaryl ring in said substitutedheteroaryl piperazine is chosen from unsubstituted, mono-, di- andtrisubstituted heteroaryls and wherein substituents are independentlychosen from hydroxy, nitro, cyano, amino, halo, sulfonamide, C₁-C₆alkyl, C₁-C₆ perfluoroalkyl, C₁-C₆ perfluoroalkoxy, C₁-C₆ alkoxy,(C₁-C₆)-alkyl-oxy-(C₁-C₆)alkoxy, mono(C₁-C₆ alkyl)amino, di(C₁-C₆alkyl)amino, mono(C₁-C₆ alkyl)amino(C₁-C₆ alkyl), and di(C₁-C₆alkyl)amino(C₁-C₆ alkyl); and R₃ is chosen from hydrogen; and straightand branched chain C₁-C₆ alkyl, in which the branched alkyl chains mayform a 3-7 member ring chosen from heteroalkyl rings and alkyl rings. 6.At least one chemical entity chosen from:1-(4-chloro-phenyl)-3-[3-(8-methylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-urea;1-(4-chloro-phenyl)-3-{3-[8-(pyridin-3-ylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea;4-(6-{3-[3-(4-chlorophenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoicacid ethyl ester; cyclopropylmethyl-[6-(4-phenoxyphenyl),imidazo[1,2-a]pyrazin-8yl]-amine;(2-methoxybenzyl)-[6-(4-phenoxyphenyl)-imidazo[1,2-a]pyrazin-8-yl]-amine;benzo[1,3]dioxol-5-ylmethyl-[6-(4-phenoxyphenyl)-imidazo[1,2-a]pyrazin-8-yl]-amine;[6-(4-(chloromethyl)phenyl)-imidazo[1,2-a]pyrazin-8-yl]-(2-methoxy-benzyl)-amine;(2-methoxy-benzyl)-{6-[4-(4-methoxybenzylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl}-amine;(2-methoxy-benzyl)-{6-[3-(4-methoxybenzylamino)-phenyl]-imidazo[1,2-a]pyrazin-8-yl}-amine;4-{6-[4-(piperidine-1-carbonyl)-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzoicacid ethyl ester;4-(6-{3-[3-(4-chlorophenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoicacid ethyl ester;4-(6-{3-[3-(2-methylsulfanyl-phenyl)-ureido]-phenyl}-imidazo[1,2-a]pyrazin-8-ylamino)-benzoicacid ethyl ester;{4-[8-(4-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-piperidin-1-yl-methanone;{4-[8-(2-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-piperidin-1-yl-methanone;and pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 7. At least one chemical entity of claim 1 chosen from1-(4-chloro-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 8. At least one chemical entity of claim 1 chosen from1-(4-chloro-phenyl)-3-{3-[8-(4-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 9. At least one chemical entity of claim 1 chosen from1-(4-chloro-phenyl)-3-{3-[8-(3-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 10. At least one chemical entity of claim 1 chosen from1-(4-chloro-phenyl)-3-{3-[8-(2-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 11. At least one chemical entity of claim 1 chosen from1-{3-[8-(4-chlorobenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 12. At least one chemical entity of claim 1 chosen from1-{3-[8-(3-chlorobenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 13. At least one chemical entity of claim 1 chosen from1-{4-[8-(4-chlorobenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 14. At least one chemical entity of claim 1 chosen from1-{4-[8-(3-chlorobenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(4-chloro-phenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 15. At least one chemical entity of claim 1 chosen from1-{4-[8-(2-methoxybenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-phenyl-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 16. At least one chemical entity of claim 1 chosen from1-{3-[8-(2-methoxybenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-phenyl-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 17. At least one chemical entity of claim 1 chosen from1-(2-chloro-phenyl)-3-{4-[8-(2-methoxybenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 18. At least one chemical entity of claim 1 chosen from1-{4-[8-(2-methoxybenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(2-methoxy-phenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 19. At least one chemical entity of claim 1 chosen from1-{4-[8-(2-ethoxybenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-methoxy-phenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 20. At least one chemical entity of claim 2 chosen from3-methoxy-N-{4-[8-(2-methoxybenzylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamideand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 21. At least one chemical entity of claim 1 chosen from1-(3-chloro-4-fluorophenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 22. At least one chemical entity of claim 1 chosen from1-(4-chlorophenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 23. At least one chemical entity of claim 1 chosen from1-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 24. At least one chemical entity of claim 1 chosen from1-(2-chloro-5-trifluoromethyl-phenyl)-3-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 25. At least one chemical entity of claim 1 chosen from1-(4-chlorophenyl)-3-{3-[8-(4-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 26. At least one chemical entity of claim 1 chosen from1-{3-[8-(4-chloro-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethylphenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 27. At least one chemical entity of claim 1 chosen from1-(3-chloro-4-fluorophenyl)-3-{3-[8-(3-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 28. At least one chemical entity of claim 1 chosen from1-(4-chlorophenyl)-3-{3-[8-(3-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 29. At least one chemical entity of claim 1 chosen from1-{3-[8-(3-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-3-(3-trifluoromethylphenyl)-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 30. At least one chemical entity of claim 1 chosen from1-(3-chloro-4-fluorophenyl)-3-{3-[8-(2-chlorophenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-ureaand pharmaceutically acceptable salts, hydrates, and diastereomersthereof.
 31. At least one chemical entity of claim 1 wherein in an invitro assay of inhibition of AKT-1 kinase, the at least one chemicalentity exhibits an IC₅₀ value less than or equal to 25 micromolar. 32.At least one chemical entity of claim 1 wherein in an in vitro assay ofmodulation of cell growth in soft agar, the at least one chemical entityexhibits an IC₅₀ value less than or equal to 25 micromolar.
 33. At leastone chemical entity of claim 1 wherein in an in vitro assay ofmodulation of cell growth in soft agar, wherein the cells are chosenfrom HCT-15, MiaPaca-2, MCF-7, OVCAR-4, and A549 cells, the at least onechemical entity exhibits an IC₅₀ value less than or equal to 25micromolar.
 34. A pharmaceutical composition comprising at least onechemical entity of claim 1; and at least one pharmaceutically acceptablecarrier or excipient.